This invention relates to a method for preventing or treating postoperative ileus by administering a composition which inhibits the action of vasopressin and/or other substances which bind to vasopressin receptors.
Gastric and colonic motility disturbances are quite common after intra-abdominal surgery. The small bowel is largely unaffected, and motility and absorption are normal within a few hours after operation. Stomach emptying is usually impaired for about 24 hours, but the colon may remain inert for 48 to 72 hours or more. This condition is known as postoperative ileus and its occurrence not only prolongs hospitalization, but also fosters postoperative complications, especially aspiration pneumonia. Symptoms and signs include abdominal distension, vomiting, obstipation, and cramps. Auscultation reveals a silent abdomen and minimum peristalsis. X-rays show gaseous distension of isolated segments of both small and large bowel. Treatment usually involves continuous nasogastric suction, nothing by mouth, intravenous (IV) fluids and electrolytes, and a minimal amount of sedatives. Sometimes colonic ileus can be relieved by colonoscopic decompression, but rarely cecostomy is required. Ileus persisting for a fill week or longer may be caused by a mechanical obstruction.
Studies using isolated canine jejunal segments have shown that following exposure to vasopressin, the jejunum becomes atonic with intraluminal pooling of perfusate. Transit time was prolonged, and intestinal absorption of water was decreased. Radionuclide imaging confirmed loss of intestinal motility. The studies concluded that the high plasma levels of vasopressin which are known to follow laparotomy may be a factor in the development of postoperative ileus.
Studies using monkeys who had strain gauge transducers implanted in the colon showed that the frequency of basal colonic contractions was reduced with increasing doses of vasopressin. The results suggest that the physiological concentrations of serum vasopressin present postoperatively may transiently inhibit colon contractions.
Vasopressin, also known as antidiuretic hormone (ADH), is a peptide synthesized in the magnocellular neurosecretory cells of the paraventricular and supraoptic nuclei of the hypothalamus, and is stored in the posterior pituitary. Vasopressin is released into the circulation in response to an increase in plasma osmolality (mediated by osmoreceptors) or a decrease in plasma volume or blood pressure (mediated by baroreceptors). However, there are other stimuli for vasopressin release, including circulating norepinephrine, angiotensin II, pain, hypoxia, nausea and vomiting, and fever. During laparoscopy a decrease in circulating plasma volume, pneumoperitoneum, and a neuronal impulse from the surgical site may result in raised levels of circulating arginine vasopressin (AVP). This rise in AVP may in turn lead to increased splachnic vascular resistance and mesenteric vasoconstriction, reduction of superior mesenteric artery blood flow and mesenteric microcirculation reduction ineffective perfusion pressure, and finally, splachnic ischemia. Splachnic ischemia, in turn, can cause an increase in splachnic free redical formation, a decrease in gut metabolic activity, and bacterial translocationxe2x80x94factors resulting in paralytic ileus.
The cellular effects of vasopressin are mediated by interaction of the hormone with two principal types of receptors, V1 and V2. V1 receptors have been subclassified further as V1a and V1b. The V1a receptor is the most widespread subtype and is found in vascular smooth muscle, myometrium, the bladder, adipocytes, hepatocytes, platelets, renal medullary interstitial cells, vasa recta in the renal microcirculation, epithelial cells in the renal cortical collecting duct, spleen, testis, and in many CNS tissues. Only the adrenohypophysis is known to contain V1b receptors. The V2 receptors are predominantly located in principal cells of the renal collecting duct system.
Vasopressin is one of the most potent vasoconstrictors known (V1 receptor mediated) and the vasopressin response to hypovolemia or hypotension serves as a mechanism to stave off cardiovascular collapse during periods of severe blood loss and/or hypotension (Laszlo, et al., Pharmacol Rev., 1991;43:73-108). Vascular smooth muscle in the skin, skeletal muscle, fat, pancreas, and thyroid gland appear most sensitive, with significant vasoconstriction also occurring in the coronary vessels, brain, and gastrointestinal tract. It has been shown (Thibonnier, 1988) that administration of a peptide V1 receptor antagonist improves hemodynamic function in patients with increased peripheral resistance due to heart failure.
We have discovered that compounds which inhibit binding of vasopressin to vasopressin receptors in the gastrointestinal tract can significantly reduce the incidence of postoperative ileus.
This invention provides a method for treating or preventing postoperative ileus comprising administering to a patient an effective amount of a vasopressin antagonist. The vasopressin antagonist to be employed is any chemical compound that is effective in inhibiting the biological activity of any known vasopressin or antidiuretic hormone. Numerous compounds are known to be vasopressin antagonists, and any of such compounds can be utilized in the method of this invention.
In a preferred embodiment, the vasopressin antagonist to be utilized is a condensed benzazepine such as those described in U.S. Pat. No. 5,723,606, incorporated herein by reference. In a further preferred embodiment, the vasopressin antagonist is an imidazo benzazepine of the Formula I: 
wherein:
R and R5 are independently hydrogen or lower alkyl;
R1, R2, and R3 independently are hydrogen, halo, lower alkyl, lower alkoxy, amino, alkylamino, or dialkylamino; and
R4 is hydrogen, phenyl or substituted phenyl, and pharmaceutically acceptable salts thereof.
An especially preferred vasopressin antagonist to be used in accordance with this invention is conivaptan, which is N-[4-(2-methyl-4,5,6- tetrahydromidazo [4,5-d][1]benzazepin-6-ylcarbonyl)phenyl]biphenyl-2-carboxamide hydrochloride. Conivaptan is also referred to as YM087 and CI-1025, and has the structural Formula II below: 
Other vasopressin antagonists that can be employed according to this invention include the benzoheterocyclic compounds described in U.S. Pat. No. 5,258,510, incorporated herein by reference. Preferred compounds from this class to be used herein include the following:
5-Dimethylamino-1-[4-(2-methylbenzoylamino)-benzoyl ]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Dimethylamino-1-[2-chloro-4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Methylamino-1-[2-chloro-4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Cyclopropylamino-1-[2-chloro-4-(2-methylbenzoylamino) benzoxyl]-2,3,4,5-tetrahydro
5-Cyclopropylamino-1-[2-chloro-4-(2-chlorobenzoylamino) benzoxyl]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Dimethylamino-1-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Dimethylamino-1-[2-methoxy4-(2-methylbenzoylamino) benzoyl]-1,2,3,4-tetrahydroquinoline;
7-Chloro-5-methylamino-1 -[4-(2-methylbenzoylamino) benzoxyl]-2,3,4,5-tetrahydro-1H-benzazepine; and
7-Chloro-5-methylamino-1-[4-(2-chlorobenzoylamino) benzoxyl]-2,3,4,5-tetrahydro-1H-benzazepine.
In Formula I above, R and R5 are hydrogen or lower alkyl. The term xe2x80x9clower alkylxe2x80x9d means a straight or branched carbon chain having from 1 to 6 carbon atoms. Typical lower alkyl groups include methyl, ethyl, isopropyl, n-butyl, neopentyl, and 1,1-dimethylbutyl.
xe2x80x9cHaloxe2x80x9d is a halogen atom such as fluoro, chloro, bromo, and iodo. xe2x80x9cLower alkoxyxe2x80x9d means the C1-C6 alkyl groups mentioned above linked through an oxygen atom. Examples of lower alkoxy include methoxy, ethoxy, isopropoxy, sec-pentyloxy, and n-hexyloxy.
The term xe2x80x9calkylaminoxe2x80x9d means an amino group (xe2x80x94NH2) substituted with one C1-C6 alkyl group. Typical alkylamino groups include methylamino, isopropylamino, n-pentylamino, and tert-butylamino. xe2x80x9cDialkylaminoxe2x80x9d means an amino group having two C1-C6 alkyl groups, for example, dimethylamino, N-ethyl-N-hexylamino, diisopropylamino, and N-butyl-N-methylamino.
R4 is hydrogen, phenyl, or substituted phenyl. The term xe2x80x9csubstituted phenylxe2x80x9d means a phenyl group substituted with 1, 2, or 3 groups selected from lower alkyl, lower alkoxy, halo, amino, alkylamino, and dialkylamino, as those terms are defined above.
Any vasopressin antagonist can be administered to a patient to prevent or treat postoperative ileus according to this invention. The term xe2x80x9cvasopressin antagonist,xe2x80x9d as is used herein, means any compound which can bind to either the vasopressin receptor site or to vasopressin itself in a manner to prevent normal vasopressin activity. The term xe2x80x9cpatientxe2x80x9d and xe2x80x9cmammalxe2x80x9d is used herein to mean an individual, including a human or animal, experiencing symptoms of postoperative ileus or an individual prior to abdominal surgery who, following surgery, has the potential to experience postoperative ileus. xe2x80x9cAbdominal surgeryxe2x80x9d means any invasion of the mammal that reaches below the chest and above the knees. The term xe2x80x9ceffective amountxe2x80x9d is used herein to mean a concentration of compound which, if administered, would prevent, reduce, or stop the symptoms or physical occurrence of postoperative ileus. Typical xe2x80x9ceffective amountsxe2x80x9d are about 1 mg/kg to about 100 mg/kg. Preclinical pharmacologic studies have demonstrated potent binding of YM087 (conivaptan) to vasopressin receptors and antagonism of the vascular and renal effects of vasopressin. YM087 has high affinity for V1a and V2 receptors with pKi (negative log of the binding inhibition constant) of 8.20 for human V1a receptors, and 8.95 for human V2 receptors expressed in COS-1 cells.
In a preferred embodiment, a vasopressin antagonist is administered to a patient prior to a scheduled abdominal surgery, for example, from 1 to 6 hours prior to surgery, or upon postoperative transfer to the recovery room or intensive care unit in order to prevent or diminish the symptoms or signs of postoperative ileus.